Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA108003 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Elevated Met receptor tyrosine kinase (RTK) expression correlates with poor outcome in breast cancer, yet a causal role for Met in the development of breast cancer has not been directly established. To examine this question, we generated a transgenic mouse model that targets expression of an oncogenic Met receptor (MetMut) to the mammary epithelium. We show that MetMut induces mammary tumors with a variety of histopathologies that exhibit gene expression profiles sharing similarities with human basal and luminal breast tumor subtypes. Among all breast cancers, we further demonstrate that the Met receptor is primarily overexpressed in human basal and HER2 positive breast cancers, and that a Met associated gene expression signature identifies patients with poor prognosis. Keywords: Met, mammary, poor outcome, EMT, basal breast cancer
2009-03-30 | GSE10450 | GEO
Project description:Elevated Met receptor tyrosine kinase (RTK) expression correlates with poor outcome in breast cancer, yet a causal role for Met in the development of breast cancer has not been directly established. To examine this question, we generated a transgenic mouse model that targets expression of an oncogenic Met receptor (MetMut) to the mammary epithelium. We show that MetMut induces mammary tumors with a variety of histopathologies that exhibit gene expression profiles sharing similarities with human basal and luminal breast tumor subtypes. Among all breast cancers, we further demonstrate that the Met receptor is primarily overexpressed in human basal and HER2 positive breast cancers, and that a Met associated gene expression signature identifies patients with poor prognosis. Experiment Overall Design: Common reference design. 26 samples (including 20 normal tissue and 32 tumor tissue samples) replicated twice as dye swaps, generating a total of 52 arrays.
2009-04-03 | E-GEOD-10450 | biostudies-arrayexpress
Project description:SUMMARY: Basal breast cancer has been associated with mutations in a number of specific tumor suppressor genes, however, the mechanism by which these tumors express a basal lineage remains unknown. Notch signaling suppresses mammary stem cell (MaSC) self-renewal, while promoting luminal cell fate specification. Here we show that Lfng, a sugar transferase that facilitates Notch activation, suppresses mammary stem/bipotent progenitor cell proliferation. Targeted deletion of Lfng in mammary epithelium induces basal tumors with reduced expression of Notch targets, amplification of the Met/Caveolin gene locus, and elevated Met and Igf-1R signaling. Human basal breast cancer, a disease associated with elevated MET receptor signaling and Caveolin protein, express low levels of LFNG. Thus, reduced LFNG expression cooperates with a Met/ Caveolin amplicon to promote basal breast disease. SIGNIFICANCE: Anti-Notch therapy is currently being tested for efficacy against basal-like breast cancer in humans. Here we report that LFNG, which controls Notch receptor activation, is consistently expressed at a low level in basal tumors and that deletion of this gene in the mouse mammary gland reduces Notch signaling, increases proliferation and induces basal mammary tumors in cooperation with amplification of the Met/Caveolin gene locus. These mutations interact to promote basal gene expression by decreasing Notch pathway activation, as well as to enhance Met and Igf-1R signaling. These pathways can be targeted at multiple levels in humans harboring basal breast cancer with amplification of MET and CAV1/2 32 array samples
2012-05-29 | E-GEOD-28712 | biostudies-arrayexpress
Project description:SUMMARY: Basal breast cancer has been associated with mutations in a number of specific tumor suppressor genes, however, the mechanism by which these tumors express a basal lineage remains unknown. Notch signaling suppresses mammary stem cell (MaSC) self-renewal, while promoting luminal cell fate specification. Here we show that Lfng, a sugar transferase that facilitates Notch activation, suppresses mammary stem/bipotent progenitor cell proliferation. Targeted deletion of Lfng in mammary epithelium induces basal tumors with reduced expression of Notch targets, amplification of the Met/Caveolin gene locus, and elevated Met and Igf-1R signaling. Human basal breast cancer, a disease associated with elevated MET receptor signaling and Caveolin protein, express low levels of LFNG. Thus, reduced LFNG expression cooperates with a Met/ Caveolin amplicon to promote basal breast disease. SIGNIFICANCE: Anti-Notch therapy is currently being tested for efficacy against basal-like breast cancer in humans. Here we report that LFNG, which controls Notch receptor activation, is consistently expressed at a low level in basal tumors and that deletion of this gene in the mouse mammary gland reduces Notch signaling, increases proliferation and induces basal mammary tumors in cooperation with amplification of the Met/Caveolin gene locus. These mutations interact to promote basal gene expression by decreasing Notch pathway activation, as well as to enhance Met and Igf-1R signaling. These pathways can be targeted at multiple levels in humans harboring basal breast cancer with amplification of MET and CAV1/2
2012-05-30 | GSE28712 | GEO
Project description:Mammary specific deletion of Lfng induces basal-like and claudin-low tumors with accumulation of Notch intracellular domain fragments, increased expression of proliferation-associated Notch targets, amplification of the Met/Caveolin locus, and elevated Met and Igf-1R signaling.
2012-05-30 | GSE35855 | GEO
Project description:Mammary specific deletion of Lfng induces basal-like and claudin-low tumors with accumulation of Notch intracellular domain fragments, increased expression of proliferation-associated Notch targets, amplification of the Met/Caveolin locus, and elevated Met and Igf-1R signaling. Tumor DNAs from Lfngflox/flox; MMTV-Cre conditional mutant mice are being compared to control DNAs from the same animals in order to identify common alterations associated with tumor progression
2012-05-29 | E-GEOD-35855 | biostudies-arrayexpress
Project description:Breast cancer is the second leading cause of cancer related death in American women. Patient care is complicated by inherent tumor heterogeneity that can be classified into at least six intrinsic subtypes. While targeted treatments are standard of care for most subtypes, there remains a clinical need for targeted therapies against basal-like tumors that are typically ‘triple negative breast cancers’. As such, the molecular mechanisms underlying basal-like tumors are under intense investigation to identify genetic drivers and possible drug targets of this subtype. Somatic p53 mutations are one of the most common genetic events in basal-like breast tumors. This genetic foundation primes cells to accumulate secondary genetic aberrations, a subset of which is predicted to promote tumorigenesis. To identify additional drivers of basal-like tumors, a comparative study between human and murine tumors was performed utilizing a p53null mammary transplant murine model. The p53null mammary transplant murine model produced a genomically diverse set of tumors, a subset of which we show resemble the human basal-like subtype. Microarray and sequencing technologies were used to interrogate the secondary genetic aberrations of these murine tumors which were then compared to human basal-like tumors to highlight conserved features. Of the ‘omic’ datasets analyzed, DNA copy number variation produced the largest number of conserved candidate driver genes. These candidate gene lists were further filtered using a DNA-RNA Pearson correlation cutoff of 0.5 and a requirement that the gene was deemed essential in at least one human basal-like cell line from a genome-wide RNA-mediated interference screen database. These steps highlighted seven potential driver genes that are at amplified loci in both murine and human basal-like tumors: Atp11a, Col4a2, Cul4a, Lamp1, Met, Pnpla6, and Tubgcp3. Inhibition of Met using Crizotinib caused Met amplified tumors to regress, confirming that this genetic event is a driver in a subset of p53null transplant mammary tumors. This study identifies MET as a driver of basal-like murine tumors, thus identifying a shared potential driver of human basal-like breast cancer. Our results also highlight the importance of comparative genomic studies for discovering drug targets and for providing models to study whether patient populations are likely to respond to selective targeted treatments.
2016-07-08 | GSE71071 | GEO
Project description:Using transgenic mouse models of breast cancer, we demonstrate that loss of ShcA signaling within mammary tumors results in extensive CD4+ T cell infiltration, activation and induction of a humoral immune response. Our studies reveal that ShcA signaling during early breast cancer progression is required to establish and maintain an immunosuppressive state that favors tumor growth. Consistent with these transgenic studies, high ShcA levels correlate with poor outcome and reduced CTL infiltration in primary human breast cancers. Conversely, elevated expression of a ShcA-regulated immune signature, generated from ShcA-null mammary tumors, is a predictor of good prognosis in HER2-positive and basal breast cancer patients. These observations define a novel role for ShcA in polarizing the immune response to facilitate tumorigenesis NIC SHC null Tumors vs. pooled MMPV-NIC reference, some replicate dye swaps
2010-10-12 | E-GEOD-18996 | biostudies-arrayexpress
Project description:Using transgenic mouse models of breast cancer, we demonstrate that loss of ShcA signaling within mammary tumors results in extensive CD4+ T cell infiltration, activation and induction of a humoral immune response. Our studies reveal that ShcA signaling during early breast cancer progression is required to establish and maintain an immunosuppressive state that favors tumor growth. Consistent with these transgenic studies, high ShcA levels correlate with poor outcome and reduced CTL infiltration in primary human breast cancers. Conversely, elevated expression of a ShcA-regulated immune signature, generated from ShcA-null mammary tumors, is a predictor of good prognosis in HER2-positive and basal breast cancer patients. These observations define a novel role for ShcA in polarizing the immune response to facilitate tumorigenesis
2010-10-12 | GSE18996 | GEO
Project description:Molecular profiling was used to classify mammary tumors that develop in MTB-IGFIR transgenic mice. It was determined that the primary mammary tumors (PMT), which develop due to elevated expression of the type I insulin-like growth factor receptor (IGF-IR) in mammary epithelial cells, most closely resemble murine tumors with basal-like or mixed gene expression profiles and with human basal-like breast cancers. Downregulation of IGF-IR transgene in MTB-IGFIR tumor-bearing mice leads to the regression of most of the tumors followed by tumor re-appearance in some of the mice. These tumors that re-appear following IGF-IR transgene downregulation do not express the IGF-IR transgene and cluster with murine mammary tumors that express a mesenchymal gene expression profile and with human claudin-low breast cancers. Therefore, IGF-IR overexpression in murine mammary epithelial cells induces mammary tumors with primarily basal-like characteristics while tumors that develop following IGF-IR downregulation express a gene signature that most closely resembles human claudin-low breast tumors. Three conditions: 8 wild type (WT) mammary glands, 11 primary mammary tumor (PMT) samples, 9 recurrent spindle tumor (RST) samples, each sample was hybridized against a universal mouse reference RNA
2011-09-30 | E-GEOD-32152 | biostudies-arrayexpress